WO2013190482A1 - Resorcinol derivatives and their cosmetic application - Google Patents

Resorcinol derivatives and their cosmetic application Download PDF

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Publication number
WO2013190482A1
WO2013190482A1 PCT/IB2013/055027 IB2013055027W WO2013190482A1 WO 2013190482 A1 WO2013190482 A1 WO 2013190482A1 IB 2013055027 W IB2013055027 W IB 2013055027W WO 2013190482 A1 WO2013190482 A1 WO 2013190482A1
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Prior art keywords
group
alkyl group
cio
chosen
dihydroxybenzyl
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PCT/IB2013/055027
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French (fr)
Inventor
Xavier Marat
Original Assignee
L'oreal
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Publication date
Application filed by L'oreal filed Critical L'oreal
Priority to CN201380032421.6A priority Critical patent/CN105408306B/en
Publication of WO2013190482A1 publication Critical patent/WO2013190482A1/en
Priority to IN2808KON2014 priority patent/IN2014KN02808A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel compounds derived from resorcinol and to a cosmetic treatment method, in particular for depigmenting and/or whitening the skin, employing such a compound.
  • blemishes which give the skin a heterogeneous appearance. These blemishes are due in particular to a high concentration of melanin in the keratinocytes situated at the surface of the skin.
  • inoffensive topical depigmenting substances which are highly effective is very particularly sought after with a view to treating pigment blemishes.
  • the mechanism of formation of the pigmentation of the skin that is to say of the formation of melanin, is particularly complex and involves, schematically, the fo Ho wing main stages :
  • Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1.14.18.1) is the essential enzyme involved in this sequence of reactions. In particular, it catalyses the conversion reaction of tyrosine to give Dopa (dihydroxyphenylalanine), by virtue of its hydroxylase activity, and the conversion reaction of Dopa to give dopaquinone, by virtue of its oxidase activity. This tyrosinase only acts when it is in the maturation state under the effect of certain biological factors.
  • a substance is recognized as depigmenting if it acts directly on the vitality of the epidermal melanocytes where melanogenesis takes place and/or if it interferes with one of the stages of the biosynthesis of melanin, either by inhibiting one of the enzymes involved in melanogenesis or by being inserted as structural analogue of one of the chemical compounds in the sequence for the synthesis of melanin, which sequence can then be blocked and thus ensure depigmentation.
  • Arbutin and kojic acid are known as depigmenting agents for the skin. Substances have been sought which exhibit an effective depigmenting action, in particular superior to that of arbutin and kojic acid. In this regard, the Applicant Company has discovered, surprisingly and unexpectedly, that some compounds derived from resorcinol exhibit a good depigmenting activity, even at low concentration.
  • a subject-matter of the invention is thus novel compounds of formula (I) as defined below.
  • compositions comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined below.
  • Another subject-matter of the invention is a non-therapeutic cosmetic method for depigmenting, lightening and/or whitening keratinous substances, in particular the skin, comprising the application of the composition described above.
  • it is the method for depigmenting, lightening and/or whitening the skin.
  • the invention also relates to the non-therapeutic cosmetic use of a compound of formula (I) as whitening, lightening and/or depigmenting agent for keratinous substances, in particular the skin.
  • the compounds according to the invention make it possible to effectively depigment and/or lighten, indeed even to whiten, the skin of human beings. They are in particular intended to be applied to the skin of individuals exhibiting brownish pigmentation blemishes or blemishes due to ageing or to the skin of individuals desiring to combat the appearance of a brownish colour originating from melanogenesis.
  • a subject-matter of the invention is thus novel compounds of formula (I) as follows: in which:
  • R denotes a hydrogen atom or an acetyl group
  • Y denotes a radical chosen from OR' or NAR"
  • R' denotes a radical chosen from:
  • a saturated linear (Ci-C2o)alkyl group an unsaturated (C 2 -C 2 o)alkyl group, a branched (C 3 -C 2 o)alkyl group or a (C 3 -Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
  • a saturated or unsaturated nonaromatic (C 3 -Cs)cycloalkyl or heterocycle group optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C 4 )alkyl group
  • c) an aryl or heteroaryl group optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group
  • R5 being chosen from
  • R6 and R7 which are identical or different, being chosen from
  • R6 and R7 it being possible for R6 and R7 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
  • A denotes a radical chosen from:
  • x a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C 8 )alkoxy group and a (Ci-C 4 )alkyl group; and
  • -NH-C NH(NH 2 ) (guanidine group); c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group; d) -NR12R13; e) -OR14; f) -C(0)NHR14; and g) -C(0)(Ci-Cio)alkyl;
  • R12 and R13 which are identical or different, denoting a radical chosen from: ⁇ -H,
  • R12 and R13 it being possible for R12 and R13 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C4)alkoxy group;
  • R14 denoting a radical chosen from:
  • R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C 2 -Cio)alkyl group, a branched (C 3 -Cio)alkyl group or a (C 3 -Cs)cycloalkyl group;
  • R16 and R17 which are identical or different, being chosen from H; an acetyl radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C 2 -Cio)alkyl group, a branched (C 3 -Cio)alkyl group or a (C 3 -C 8 )cycloalkyl group; and a phenyl(Ci-C 4 )alkyl group, such as a benzyl group, or a pyridyl(Ci-C 4 )alkyl group;
  • R16 and R17 it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
  • R" denotes a radical chosen from:
  • aryl or heteroaryl group optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
  • R25 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C 2 -Cio)alkyl group, a branched (C 3 -Cio)alkyl group or a (C 3 -Cs)cycloalkyl group;
  • R26 and R27 which are identical or different, being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C 2 -Cio)alkyl group, a branched (C 3 - Cio)alkyl group or a (C 3 -C 8 )cycloalkyl group; a phenyl(Ci-C 4 )alkyl group, such as a benzyl group, or a pyridyl(Ci-C 4 )alkyl group;
  • R26 and R27 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-Cio)alkyl, hydroxy(Ci- Cio)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-Cio)alkyl group and a branched (C 3 -Cio)alkyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
  • the salts of the compounds of formula (I) comprise conventional non-toxic salts of the said compounds, such as those formed from acid or base.
  • salts of the compound of formula (I) when it comprises a quaternizable nitrogen atom, of: a) the salts obtained by addition of the compound (I) to an inorganic acid, chosen in particular from hydrochloric, boric, hydrobromic, hydriodic, sulfuric, nitric, carbonic, phosphoric or tetrafluoroboric acid;
  • the salts obtained by addition of the compound (I) to an organic acid chosen in particular from acetic, propionic, succinic, fumaric, lactic, gly colic, citric, gluconic, salicylic, tartaric, terephthalic, methylsulfonic, ethylsulfonic, benzenesulfonic, toluenesulfonic or triflic acid.
  • organic acid chosen in particular from acetic, propionic, succinic, fumaric, lactic, gly colic, citric, gluconic, salicylic, tartaric, terephthalic, methylsulfonic, ethylsulfonic, benzenesulfonic, toluenesulfonic or triflic acid.
  • salts obtained by addition of the compound of formula (I) (when it comprises an acid group) to an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide, and the carbonates or hydrogencarbonates of sodium, of potassium or of calcium, for example;
  • a primary, secondary or tertiary alkylamine for example triethylamine or butylamine.
  • This primary, secondary or tertiary alkylamine can comprise one or more nitrogen and/or oxygen atoms and can thus comprise, for example, one or more alcohol functional groups; mention may in particular be made of 2-amino-2- methylpropanol, ethanolamine, triethanolamine, 2-(dimethylamino)propanol, 2-amino-2-
  • the salts of amino acids such as, for example, lysine, arginine, guanidine, glutamic acid or aspartic acid.
  • the salts of the compound of formula (I) can be chosen from alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium; or ammonium salts.
  • the salts of the compound of formula (I) can be chosen from halides, such as chloride or bromide, citrate, acetate, succinate, phosphate, lactate or tartrate.
  • the acceptable solvates of the compounds described in the present invention comprise conventional solvates, such as those formed during the preparation of the said compounds due to the presence of solvents. Mention may be made, by way of example, of the solvates due to the presence of water or of linear or branched alcohols, such as ethanol or isopropanol.
  • optical isomers are in particular enantiomers and diastereoisomers.
  • optical isomers are in particular enantiomers and diastereoisomers.
  • (C x -C y )alkyl group denotes an alkyl group comprising from x to y carbon atoms.
  • Such an alkyl group can be linear and saturated and can typically include from 1 to 20 carbon atoms or also from 1 to 10 carbon atoms. It can also be linear and unsaturated and can typically include from 2 to 20 carbon atoms or also from 2 to 10 carbon atoms. It can also be branched and can typically include from 3 to 20 carbon atoms or also from 3 to 10 carbon atoms.
  • An alkyl group can also be cyclic; it is then a cycloalkyl group, which can typically include from 3 to 8 carbon atoms.
  • a "(C x -C y )alkyl group” denotes a saturated and linear alkyl group comprising from x to y carbon atoms.
  • the branched or saturated linear alkyl groups can be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2- ethylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
  • the branched or saturated linear alkyl groups can be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2- ethylhexyl and octyl.
  • the cycloalkyl group can be chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • (C x -C y )alkoxy group denotes a linear and if appropriate branched group of formula -0(C x -C y )alkyl which can typically include from 1 to 8 carbon atoms or also from 1 to 4 carbon atoms.
  • the alkoxy group can be chosen from methoxy, ethoxy, propoxy and butoxy and can more particularly be a methoxy group.
  • a “saturated or unsaturated nonaromatic heterocycle group” denotes a monocyclic or bicyclic carbocyclic group having from 5 to 8 ring members and comprising from one to three heteroatoms or groups chosen from N, O, S and -C(O)-.
  • a heterocycle group can be chosen from piperidyl, morpholinyl, piperazinyl and pyrrolidinyl. Preferably, it is the piperidyl or morpholinyl ring.
  • aryl group denotes an unsaturated or partially unsaturated monocyclic or bicyclic carbocyclic group including from 5 to 12 carbon atoms.
  • the aryl radicals can be chosen from phenyl, naphthyl, indenyl, fluorenyl and anthracenyl. Preferably, it is the phenyl group.
  • heteroaryl group denotes a fused or nonfused poly- or monocyclic group comprising from 5 to 22 ring members and from 1 to 6 heteroatoms chosen from a nitrogen, oxygen or sulfur atom, at least one ring of which is aromatic.
  • the heteroaryl radicals can be chosen from furyl, acridinyl, benzimidazolyl, benzobistriazolyl, benzopyrazolyl, benzopyridazinyl, benzoquinolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, pyridinyl, tetrazolyl, dihydrothiazolyl, imidazopyridinyl, imidazolyl, indolyl, isoquinolyl, naphthoimidazolyl, naphthooxazolyl, naphthopyrazolyl, oxadiazolyl, oxazolyl, oxazolopyridyl, phenazinyl, phenooxazolyl, pyrazinyl, pyrazolyl, pyrazoyltriazyl, pyridyl, pyridinoimidazolyl, pyrrolyl, quinolyl, t
  • R denotes a hydrogen atom or an acetyl group
  • Y denotes a radical chosen from OR' or NAR"
  • R' denotes a radical chosen from:
  • R5 being chosen from H and a saturated linear (Ci-C4)alkyl group
  • A denotes a radical chosen from: a) -H; b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C 2 -C 2 o)alkyl group, a branched (C 3 -C 2 o)alkyl group or a (C 3 -Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
  • a saturated or unsaturated nonaromatic (C 3 -Cs)cycloalkyl or heterocycle group optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C 4 )alkyl group
  • c) an aryl or heteroaryl group optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group
  • d) -NR12R13; and e) -OR14
  • R12 and R13 which are identical or different, denoting a radical chosen from:
  • R12 and R13 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C 4 )alkoxy group; R14 denoting a radical chosen from:
  • a saturated linear (Ci-Cio)alkyl group which can optionally be substituted by one to three identical or different groups chosen from a saturated linear (Ci-Cio)alkyl group, optionally substituted by one or more phenyl radicals, it being possible for the said phenyl radicals to be optionally substituted by one to three identical or different groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
  • R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C 3 -Cio)alkyl group and a (C 3 -Cs)cycloalkyl group;
  • R16 and R17 which are identical or different, being chosen from
  • a saturated linear (Ci-Cio)alkyl group an unsaturated (C 2 -Cio)alkyl group, a branched (C 3 -Cio)alkyl group or a (C 3 -C8)cycloalkyl group; and a phenyl(Ci-C 4 )alkyl group, such as a benzyl group, or a pyridyl(Ci-C 4 )alkyl group;
  • R16 and R17 it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
  • R" denotes a radical chosen from:
  • R denotes a hydrogen atom
  • Y denotes a radical chosen from OR' or NAR"
  • R' denotes a radical chosen from:
  • A denotes a radical chosen from:
  • an aryl or heteroaryl group optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, preferably an imidazole or indole radical or a phenyl radical optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, particularly preferably an imidazolyl, indolyl or phenyl group, and
  • Cs)cycloalkyl or heterocycle group optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group;
  • a phenyl group optionally substituted by one to three groups chosen from hydroxyl, methoxy and ethoxy; d) -NR12R13; and e) -OR14; R12 and R13, which are identical or different, denoting a radical chosen from:
  • a phenyl group optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group;
  • R12 and R13 preferably denoting a hydrogen atom or a (Ci-C4)alkyl group
  • R14 denoting a radical chosen from:
  • a saturated linear (Ci-C4)alkyl group optionally substituted by a phenyl radical, such as the benzyl group;
  • R15 being chosen from H, a saturated linear (Ci-C 4 )alkyl group and a branched (C 3 -C 4 )alkyl group;
  • R16 and R17 which are identical or different, being chosen from H; an acetyl radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C 3 -Cio)alkyl group or a (C 3 -C8)cycloalkyl group; and a phenyl(Ci-C 4 )alkyl group, such as a benzyl group, or a pyridyl(Ci-C 4 )alkyl group;
  • R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle comprising one to three heteroatoms or groups chosen from N, O and -C(O)-, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
  • R" denotes a radical chosen from:
  • R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-C 4 )alkyl, hydro xy(Ci- C 4 )alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-C6)alkyl group and a branched (C 3 -Ce)alkyl group, the said heterocycle preferably being a piperidinyl or morpholinyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
  • R H for the compounds of formula (I).
  • A saturated linear (Ci-Cio)alkyl, optionally substituted by a
  • A saturated linear (Ci-Cio)alkyl, interrupted by an oxygen atom and optionally substituted by a
  • A saturated linear (Ci-Cio)alkyl, substituted by
  • R16 being chosen from H, a saturated linear (Ci-Cio)alkyl hydrocarbon group and a branched (C3-Cio)alkyl group, and
  • R15 being a saturated linear (Ci-Cio)alkyl group
  • A saturated linear (Ci-Cio)alkyl, substituted by a group chosen from iii) -NR16R17,
  • phenyl optionally being substituted by a hydroxyl and/or a (Ci-Cs ix) a heteroaryl having from 5 to 12 ring members, comprising an oxygen atom,
  • x) a saturated heterocycle having from 5 to 8 ring members, comprising one or two oxygen atoms, optionally substituted by one or two (Ci-C4)alkyl radicals,
  • R16 and R17 which are identical or different, being chosen from H, a saturated linear (Ci-Cio)alkyl group and an acetyl;
  • A branched (C 3 -Cio)alkyl, optionally substituted by a group chosen from i) hydroxyl,
  • R16 being chosen from H, a saturated linear (Ci-Cio)alkyl group and a branched (C 3 -Cio)alkyl group;
  • A cyclic (C 3 -Cs)alkyl
  • A phenyl optionally substituted by a hydroxyl
  • a and R' ' form, with the nitrogen atom which carries them, a saturated 5- to 8- membered heterocycle, optionally comprising an oxygen atom and optionally being substituted by a C(0)OT group, T denoting a saturated linear (Ci-Cio)alkyl group;
  • A denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by one or two groups chosen from
  • R16 being a saturated linear (Ci-Cio)alkyl group
  • R" denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by one or two groups chosen from i) hydroxyl,
  • R26 being a saturated linear (Ci-Cio)alkyl group
  • A saturated linear (Ci-Cio)alkyl
  • A -NR12R13 or
  • R12 and R13 which are identical, denoting a radical chosen from: a) -H and
  • R14 denoting a radical chosen from:
  • the particularly preferred compounds are the compounds 52, 53, 54 and 55.
  • R H
  • Y -OR'
  • R' saturated linear (Ci-Cio)alkyl or a branched (C3-Cio)alkyl group, optionally interrupted by an oxygen atom and optionally substituted by one or two
  • the particularly preferred compounds are the compounds 56 and 61.
  • the compounds of the invention can be prepared according to the following
  • Ri denotes H or a linear (Ci-C6)alkyl group or a branched (C 3 - C 6 )alkyl group, in order to form a compound C, b) reduction of this compound C, in order to result in the intermediate (III), then
  • An alternative form consists in treating (III) with an alcohol ROH, in order to result in the compounds (IV), which, by reaction with YH, result in the compounds of formula (I).
  • Another subject-matter of the invention is the compound of formula (III) and the compound of formula (IV)
  • R denotes H or a linear (Ci-C 6 )alkyl group or a branched (C3-C 6 )alkyl group.
  • ROH denotes ethanol and the R radical of the compound of formula (IV) denotes the ethyl radical.
  • reaction of resorcinol (Al) with itaconic acid (B) or its anhydride ( ⁇ ') or one of its esters of formula (B l) which are described above, in order to form the compound C is carried out in particular in the presence of an organic solvent which can be chosen from toluene, tetrahydrofuran, heptane, isooctane, methyltetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate, isododecane and their mixtures, in particular at a temperature of between 15 and 200°C, optionally in the presence of a catalyst (acidic or basic) as described in the publications: Synthesis of 7- hydroxycoumarins by Pechmann reaction using Nafion resin/silica nanocomposites as catalysts: Laufer MC, Hausmann H and Holderich WF, J.
  • the compounds (Bl) can be obtained in a known way by selective esterification in an acidic medium of itaconic acid with one or more alcohols of formula ROH, as described in the literature (Selective esterification of non-conjugated carboxylic acids in the presence of conjugated or aromatic carboxylic acids over active carbon supported methanesulfonic acid; Feng, Ze Wang, Zhao, Xin Qi and Bi, Hua, Science in China, Series B: Chemistry (2008), 1(10), 990-992 / An efficient and regiospecific esterification of dioic acids using PTSA; Devi, A.
  • the compound of formula (I) can be obtained by activation of the acid C according to the known methods for the activation of acids, in particular described in Comprehensive Organic Transformations by R. Larock, Wiley VCH Ed., in the chapter Interconversion of nitriles, carboxylic acids and derivatives.
  • the compound C in the acid form can be subjected to a reduction using hydride in order to result in the compound of formula (III) after acid treatment, according to the following Scheme 2.
  • This reduction can be carried out between -30 and +60°C in protic or aprotic solvents (tetrahydrofuran, dioxane, ethanol, methanol) with metal hydride donors, such as sodium borohydride, sodium triacetoxyborohydride or diisobutylaluminium hydride.
  • protic or aprotic solvents tetrahydrofuran, dioxane, ethanol, methanol
  • metal hydride donors such as sodium borohydride, sodium triacetoxyborohydride or diisobutylaluminium hydride.
  • This reaction can optionally be carried out in the presence of an organic solvent, in particular tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2- methyltetrahydrofuran, dichloromethane, toluene, methanol or ethanol,
  • an organic solvent in particular tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2- methyltetrahydrofuran, dichloromethane, toluene, methanol or ethanol,
  • a catalyst chosen from acid catalysts of Lewis or Bronsted type or basic catalysts, such as potassium carbonate, triethylamine or diisopropy lethy lamine ; optionally by heating to a temperature of between 15°C and 200°C, in particular between 30°C and 150°C.
  • lactone (III) can be in equilibrium with the ethyl ester form (III') in the presence of ethanol.
  • the acyclic ester can then react with YH compounds in order to result in the compounds (I).
  • the acetylation reaction can be carried out with acetic anhydride or acetyl chloride, in particular in the presence of an aprotic solvent, such as toluene, pyridine or tetrahydrofuran.
  • an aprotic solvent such as toluene, pyridine or tetrahydrofuran.
  • the acetylation reaction can be selective by employing protective groups on the functional groups which must not be acetylated and by then carrying out a deprotection reaction, according to the known techniques of organic synthesis.
  • these compounds when the final compounds (I) exhibit a free carboxylic acid on the A or R" radical, these compounds can be obtained by saponification using inorganic bases, such as, for example, NaOH or LiOH, in the presence of protic or aprotic solvents, such as, for example, ethanol or tetrahydrofuran or water, at temperatures varying between 0 and 100°C.
  • inorganic bases such as, for example, NaOH or LiOH
  • protic or aprotic solvents such as, for example, ethanol or tetrahydrofuran or water
  • the salts obtained are then re-acidified in the presence of conventional inorganic or organic acids, such as, for example, hydrochloric acid or citric acid.
  • the compounds of formula (I) according to the invention have a very particular application in the cosmetics field.
  • composition according to the invention comprises, in a physiologically acceptable medium, a compound of formula (I) as described above.
  • physiologically acceptable medium is understood to mean a medium compatible with human keratinous substances, such as the skin of the body or of the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and/or the hair.
  • the compound (I) can be present in the composition according to the invention in an amount which can be between 0.01% and 10% by weight, preferably between 0.1% and 5% by weight, in particular from 0.5% to 3% by weight, with respect to the total weight of the composition.
  • composition according to the invention is advantageously a cosmetic composition: it can comprise adjuvants normally employed in the cosmetics field.
  • oils in particular hydrocarbon oils or silicone oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers, cosmetic active agents, UV screening agents, polymers, thickeners, preservatives, fragrances, bactericides, ceramides, odour absorbers or antioxidants.
  • optional cosmetic adjuvants can be present in the composition in a proportion of 0.001% to 80%> by weight, in particular of 0.1 % to 40%> by weight, with respect to the total weight of the composition.
  • these adjuvants, and their proportions will be chosen by a person skilled in the art so that the advantageous properties of the compounds according to the invention are not, or not substantially, detrimentally affected by the envisaged addition.
  • retinol and its derivatives such as retinyl palmitate; ascorbic acid and its derivatives, such as magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and its derivatives, such as tocopheryl acetate; nicotinic acid and its precursors, such as nicotinamide; ubiquinone; glutathione and its precursors, such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and in particular plant proteins and their hydro lysates, and also phyto hormones; marine extracts, such as algal extracts; bacterial extracts; sapogenins, such as diosgenin, and wild yam extracts comprising same; ceramides; hydroxy acids, such as salicylic acid and 5-(n- octanoyl)salicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acylated derivative
  • treating agent is understood to mean any compound capable of having an effect:
  • ⁇ -hydroxy acids in particular salicylic acid and its derivatives (including 5-(n-octanoyl)salicylic acid); a-hydroxy acids, such as gly colic, citric, lactic, tartaric, malic or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; or resveratrol;
  • corneodesmosomes such as glycosidases, stratum corneum chymotryptic enzyme (SCCE) or indeed even other proteases (trypsin, chymotrypsin-like).
  • SCCE stratum corneum chymotryptic enzyme
  • trypsin, chymotrypsin-like enzymes involved in desquamation or decomposition of the corneodesmosomes, such as glycosidases, stratum corneum chymotryptic enzyme (SCCE) or indeed even other proteases (trypsin, chymotrypsin-like).
  • SCCE stratum corneum chymotryptic enzyme
  • agents which chelate inorganic salts include EDTA; N-acyl-N,N',N'-ethylenediaminetriacetic acid; amino sulfonic compounds, in particular N-(2-hydroxyethyl)piperazine-N'-2- ethanesulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid (procysteine) derivatives; derivatives of a-amino acids of glycine type (such as described in EP 0 852 949, and also sodium methyl glycine diacetate, sold by BASF under the trade name Trilon M); honey; or sugar derivatives, such as O-octanoyl-6-D-maltose and N- acetylglucosamine.
  • the desquamating agents are generally present in the composition according to the invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from 0.1% to 10% by weight, with respect to the total weight of the composition.
  • the soothing agents are generally present in the composition according to the invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from 0.1 %> to 10%) by weight, with respect to the total weight of the composition.
  • the organic photoprotective agents are chosen in particular from anthranilates; cinnamic derivatives; dibenzoylmethane derivatives; salicylic derivatives; camphor derivatives; triazine derivatives, such as those described in Patent Applications US 4 367 390, EP 863 145, EP 517 104, EP 570 838, EP 796 851, EP 775 698, EP 878 469, EP 933 376, EP 507 691, EP 507 692, EP 790 243 and EP 944 624; benzophenone derivatives; ⁇ , ⁇ -diphenylacrylate derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzazolyl derivatives, such as described in Patents EP 669 323 and US 2 463 264; p-aminobenzoic acid (PABA) derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives, such as described in Applications
  • the inorganic photoprotective agents can be chosen in particular from coated or non-coated metal oxide pigments or nanopigments (mean size of the primary particles generally of between 5 nm and 100 nm, preferably between 10 nm and 50 nm), such as, for example, titanium oxide (amorphous or crystallized in rutile and/or anatase form), iron oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments, which are all well- known UV photoprotective agents.
  • Conventional coating agents are furthermore alumina and/or aluminium stearate.
  • Such coated or non-coated metal oxide nanopigments are described in particular in Patent Applications EP 518 772 and EP 518 773.
  • the photoprotective agents are generally present in the composition according to the invention in proportions ranging from 0.1% to 20% by weight, preferably ranging from 0.2% to 15% by weight, with respect to the total weight of the composition.
  • composition according to the invention can be provided in all the formulation forms normally used in the cosmetics field and in particular in the form of an aqueous or aqueous/alcoholic solution, which is optionally gelled, of a dispersion of the lotion type, optionally comprising two phases, of an oil-in-water or water-in-oil or multiple (W/O/W or 0/W/O, for example) emulsion, of an aqueous gel, of a dispersion of oil in an aqueous phase using spherules, it being possible for these spherules to be polymeric nanoparticles, such as nanospheres and nanocapsules or better still lipid vesicles of ionic and/or non-ionic type, or of an aqueous or oily gel.
  • These compositions are prepared according to the usual methods. Use is preferably made, according to this invention, of a composition in the form of an emulsion, in particular an oil-in-water emulsion.
  • the composition according to the invention can constitute a composition for caring for the skin and in particular a cleansing, protecting, treating or care cream for the face, for the hands, for the feet, for the major anatomical folds or for the body (for example, day creams, night creams, make-up-removing creams, foundation creams or anti- sun creams); a fluid foundation; a make-up-removing milk, a protective or care body milk or an anti-sun milk; or a lotion, gel or mousse for caring for the skin, such as a cleansing lotion.
  • a cleansing, protecting, treating or care cream for the face, for the hands, for the feet, for the major anatomical folds or for the body for example, day creams, night creams, make-up-removing creams, foundation creams or anti- sun creams
  • a fluid foundation for example, day creams, night creams, make-up-removing creams, foundation creams or anti- sun creams
  • a fluid foundation for example, day creams, night creams, make-up-removing cream
  • the compound of formula (III) is subsequently reacted according to Scheme 3 described above with the YH compound, used as reactant and solvent when YH is liquid, for example when YH is an amine (3 equivalents), and then the reaction medium is brought to 60°C for 2h.
  • methyltetrahydrofuran can be added in a sufficient amount to dissolve the reaction medium.
  • the reaction medium is concentrated under vacuum.
  • the crude product is dissolved in methyltetrahydrofuran, washed with a 0.1N hydrochloric acid solution and then washed with water.
  • the organic phase is collected, dried over sodium sulfate and concentrated under vacuum.
  • the crude product is purified on a chromatography column to give the expected product.
  • Example 4 synthesis of compound 5 (saponification of compound 6)
  • Example 34 Example of separation of the diastereoisomers and characterization of the latter
  • test compound For the test compound, the following were determined:
  • the inhibitory activity on melanin synthesis by estimating the ratio of the incorporation of thiouracil to the incorporation of leucine, relative to 100% for the control (the control corresponds to the test carried out without test compound).
  • the IC 50 concentration for which 50% of the synthesis of the melanin is inhibited values were determined.
  • the compounds according to the invention are thus shown to be effective in inhibiting melanogenesis and are furthermore more effective than arbutin and kojic acid.
  • Example 36 Use of a cosmetic formulation
  • a depigmenting gel for the skin comprising (% by weight):
  • Carbomer (Carbopol 981 from Lubrizol) 1%
  • composition applied to the skin, makes it possible to soften brown blemishes.

Abstract

The present invention relates to a compound of formula (I): in which: Rdenotes a hydrogen atom or an acetyl group; and Ydenotes a radical chosen from OR' or NAR''; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures. It also relates to their cosmetic use, in particular as depigmenting agent, and to the associated cosmetic method.

Description

RESORCINOL DERIVATIVES AND THEIR COSMETIC APPLICATION
The present invention relates to novel compounds derived from resorcinol and to a cosmetic treatment method, in particular for depigmenting and/or whitening the skin, employing such a compound.
At different periods in their lives, some people witness the appearance on the skin and more especially on the hands and face of darker and/or more highly coloured blemishes which give the skin a heterogeneous appearance. These blemishes are due in particular to a high concentration of melanin in the keratinocytes situated at the surface of the skin.
The use of inoffensive topical depigmenting substances which are highly effective is very particularly sought after with a view to treating pigment blemishes.
The mechanism of formation of the pigmentation of the skin, that is to say of the formation of melanin, is particularly complex and involves, schematically, the fo Ho wing main stages :
Tyrosine— > Dopa— > Dopaquinone— > Dopachrome— > Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1.14.18.1) is the essential enzyme involved in this sequence of reactions. In particular, it catalyses the conversion reaction of tyrosine to give Dopa (dihydroxyphenylalanine), by virtue of its hydroxylase activity, and the conversion reaction of Dopa to give dopaquinone, by virtue of its oxidase activity. This tyrosinase only acts when it is in the maturation state under the effect of certain biological factors.
A substance is recognized as depigmenting if it acts directly on the vitality of the epidermal melanocytes where melanogenesis takes place and/or if it interferes with one of the stages of the biosynthesis of melanin, either by inhibiting one of the enzymes involved in melanogenesis or by being inserted as structural analogue of one of the chemical compounds in the sequence for the synthesis of melanin, which sequence can then be blocked and thus ensure depigmentation.
Arbutin and kojic acid are known as depigmenting agents for the skin. Substances have been sought which exhibit an effective depigmenting action, in particular superior to that of arbutin and kojic acid. In this regard, the Applicant Company has discovered, surprisingly and unexpectedly, that some compounds derived from resorcinol exhibit a good depigmenting activity, even at low concentration.
A subject-matter of the invention is thus novel compounds of formula (I) as defined below.
Another subject-matter of the invention is a composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined below.
Another subject-matter of the invention is a non-therapeutic cosmetic method for depigmenting, lightening and/or whitening keratinous substances, in particular the skin, comprising the application of the composition described above.
More preferably, it is the method for depigmenting, lightening and/or whitening the skin.
The invention also relates to the non-therapeutic cosmetic use of a compound of formula (I) as whitening, lightening and/or depigmenting agent for keratinous substances, in particular the skin.
The compounds according to the invention make it possible to effectively depigment and/or lighten, indeed even to whiten, the skin of human beings. They are in particular intended to be applied to the skin of individuals exhibiting brownish pigmentation blemishes or blemishes due to ageing or to the skin of individuals desiring to combat the appearance of a brownish colour originating from melanogenesis.
They can also make it possible to depigment and/or lighten non-scalp hair, the eyelashes or the hair, and also the lips and/or the nails.
A subject-matter of the invention is thus novel compounds of formula (I) as follows:
Figure imgf000003_0001
in which:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR"; R' denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR5,
ii) -SR5,
iii) -NR6R7,
iv) -C(0)NHR6,
v) -C(0)NR6R7,
vi) -C(0)OR6,
vii) -NHC(0)NHR6,
viii) -C(0)(Ci-C4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group; c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group; R5 being chosen from
• H, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group;
R6 and R7, which are identical or different, being chosen from
• H,
• an acetyl radical, and • a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R6 and R7 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
v) -C(0)NR16R17,
vi) -C(0)OR16,
vii) -NHC(0)NHR16,
viii) -C(0)(Ci-C4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group,
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; and
xi) -NH-C=NH(NH2) (guanidine group); c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group; d) -NR12R13; e) -OR14; f) -C(0)NHR14; and g) -C(0)(Ci-Cio)alkyl;
R12 and R13, which are identical or different, denoting a radical chosen from: · -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different -OR 15 groups, and
• an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group,
it being possible for R12 and R13 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C4)alkoxy group;
R14 denoting a radical chosen from:
· -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
vi) -C(0)OR16, and
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and • an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group;
R16 and R17, which are identical or different, being chosen from H; an acetyl radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR25,
ii) -SR25,
iii) -NR26R27,
iv) -C(0)NHR26,
v) -C(0)NR26R27,
vi) -C(0)OR26,
vii) -NHC(0)NHR26,
viii) -C(0)(Ci-C4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; and
c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R25 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group;
R26 and R27, which are identical or different, being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3- Cio)alkyl group or a (C3-C8)cycloalkyl group; a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R26 and R27 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-Cio)alkyl, hydroxy(Ci- Cio)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-Cio)alkyl group and a branched (C3-Cio)alkyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
The salts of the compounds of formula (I) comprise conventional non-toxic salts of the said compounds, such as those formed from acid or base.
Mention may be made, as salts of the compound of formula (I) (when it comprises a quaternizable nitrogen atom), of: a) the salts obtained by addition of the compound (I) to an inorganic acid, chosen in particular from hydrochloric, boric, hydrobromic, hydriodic, sulfuric, nitric, carbonic, phosphoric or tetrafluoroboric acid;
b) or the salts obtained by addition of the compound (I) to an organic acid, chosen in particular from acetic, propionic, succinic, fumaric, lactic, gly colic, citric, gluconic, salicylic, tartaric, terephthalic, methylsulfonic, ethylsulfonic, benzenesulfonic, toluenesulfonic or triflic acid.
Mention may also be made of the salts obtained by addition of the compound of formula (I) (when it comprises an acid group) to an inorganic base, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide, and the carbonates or hydrogencarbonates of sodium, of potassium or of calcium, for example;
or to an organic base, such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. This primary, secondary or tertiary alkylamine can comprise one or more nitrogen and/or oxygen atoms and can thus comprise, for example, one or more alcohol functional groups; mention may in particular be made of 2-amino-2- methylpropanol, ethanolamine, triethanolamine, 2-(dimethylamino)propanol, 2-amino-2-
(hydroxymethyl)- 1 ,3 -propanediol or 3-(dimethylamino)propylamine.
Mention may also be made of the salts of amino acids, such as, for example, lysine, arginine, guanidine, glutamic acid or aspartic acid. Advantageously, the salts of the compound of formula (I) (when it comprises an acid group) can be chosen from alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium; or ammonium salts.
Advantageously, the salts of the compound of formula (I) (when it comprises a quaternizable nitrogen atom) can be chosen from halides, such as chloride or bromide, citrate, acetate, succinate, phosphate, lactate or tartrate.
The acceptable solvates of the compounds described in the present invention comprise conventional solvates, such as those formed during the preparation of the said compounds due to the presence of solvents. Mention may be made, by way of example, of the solvates due to the presence of water or of linear or branched alcohols, such as ethanol or isopropanol.
The optical isomers are in particular enantiomers and diastereoisomers. In the context of the present invention:
- a "(Cx-Cy)alkyl group" denotes an alkyl group comprising from x to y carbon atoms. Such an alkyl group can be linear and saturated and can typically include from 1 to 20 carbon atoms or also from 1 to 10 carbon atoms. It can also be linear and unsaturated and can typically include from 2 to 20 carbon atoms or also from 2 to 10 carbon atoms. It can also be branched and can typically include from 3 to 20 carbon atoms or also from 3 to 10 carbon atoms. An alkyl group can also be cyclic; it is then a cycloalkyl group, which can typically include from 3 to 8 carbon atoms.
Unless otherwise indicated, a "(Cx-Cy)alkyl group" denotes a saturated and linear alkyl group comprising from x to y carbon atoms.
Preferably, the branched or saturated linear alkyl groups can be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2- ethylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
More preferably, the branched or saturated linear alkyl groups can be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2- ethylhexyl and octyl.
The cycloalkyl group can be chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- A "(Cx-Cy)alkoxy group" denotes a linear and if appropriate branched group of formula -0(Cx-Cy)alkyl which can typically include from 1 to 8 carbon atoms or also from 1 to 4 carbon atoms.
The alkoxy group can be chosen from methoxy, ethoxy, propoxy and butoxy and can more particularly be a methoxy group.
- A "saturated or unsaturated nonaromatic heterocycle group" denotes a monocyclic or bicyclic carbocyclic group having from 5 to 8 ring members and comprising from one to three heteroatoms or groups chosen from N, O, S and -C(O)-.
A heterocycle group can be chosen from piperidyl, morpholinyl, piperazinyl and pyrrolidinyl. Preferably, it is the piperidyl or morpholinyl ring.
- An "aryl group" denotes an unsaturated or partially unsaturated monocyclic or bicyclic carbocyclic group including from 5 to 12 carbon atoms. The aryl radicals can be chosen from phenyl, naphthyl, indenyl, fluorenyl and anthracenyl. Preferably, it is the phenyl group.
- A "heteroaryl group" denotes a fused or nonfused poly- or monocyclic group comprising from 5 to 22 ring members and from 1 to 6 heteroatoms chosen from a nitrogen, oxygen or sulfur atom, at least one ring of which is aromatic.
The heteroaryl radicals can be chosen from furyl, acridinyl, benzimidazolyl, benzobistriazolyl, benzopyrazolyl, benzopyridazinyl, benzoquinolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, pyridinyl, tetrazolyl, dihydrothiazolyl, imidazopyridinyl, imidazolyl, indolyl, isoquinolyl, naphthoimidazolyl, naphthooxazolyl, naphthopyrazolyl, oxadiazolyl, oxazolyl, oxazolopyridyl, phenazinyl, phenooxazolyl, pyrazinyl, pyrazolyl, pyrazoyltriazyl, pyridyl, pyridinoimidazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolopyridinyl, thiazoylimidazolyl, thiopyrylyl, triazolyl, xanthyl and its ammonium salt. Preferably, the compounds of formula (I) have the following meanings:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H; b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different -OR5 groups; and c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from H and a saturated linear (Ci-C4)alkyl group;
A denotes a radical chosen from: a) -H; b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
vi) -C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group; c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group; d) -NR12R13; and e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H;
• a saturated linear (Ci-C4)alkyl group; and
• a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group; and
it being possible for R12 and R13 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C4)alkoxy group; R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-Cio)alkyl group which can optionally be substituted by one to three identical or different groups chosen from a saturated linear (Ci-Cio)alkyl group, optionally substituted by one or more phenyl radicals, it being possible for the said phenyl radicals to be optionally substituted by one to three identical or different groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group and a (C3-Cs)cycloalkyl group;
R16 and R17, which are identical or different, being chosen from
• H;
• an acetyl radical; and
· a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-Cio)alkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different -OR25 groups; R25 being chosen from H or a linear (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-C4)alkyl, hydroxy(Ci- C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-C6)alkyl group and a branched (C3-C6)alkyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
More preferably, the compounds of formula (I) have the following meanings:
R denotes a hydrogen atom;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H; and b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three oxygen atoms, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from hydroxyl, methoxy and ethoxy; A denotes a radical chosen from:
a) -H; b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three oxygen atoms, it being possible for the said groups to be optionally substituted by one or more identical or different groups chosen from: i) -OR15,
ii) -SR15, preferably SMe,
iii) -NR16R17,
vi) -C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, preferably an imidazole or indole radical or a phenyl radical optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, particularly preferably an imidazolyl, indolyl or phenyl group, and
x) a saturated or unsaturated nonaromatic, preferably saturated, (C3-
Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group;
c) a phenyl group optionally substituted by one to three groups chosen from hydroxyl, methoxy and ethoxy; d) -NR12R13; and e) -OR14; R12 and R13, which are identical or different, denoting a radical chosen from:
• -H,
• a saturated linear (Ci-C4)alkyl group, and
• a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group;
R12 and R13 preferably denoting a hydrogen atom or a (Ci-C4)alkyl group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-C4)alkyl group, optionally substituted by a phenyl radical, such as the benzyl group; R15 being chosen from H, a saturated linear (Ci-C4)alkyl group and a branched (C3-C4)alkyl group;
R16 and R17, which are identical or different, being chosen from H; an acetyl radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle comprising one to three heteroatoms or groups chosen from N, O and -C(O)-, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different -OR25 groups;
R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-C4)alkyl, hydro xy(Ci- C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-C6)alkyl group and a branched (C3-Ce)alkyl group, the said heterocycle preferably being a piperidinyl or morpholinyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
Preferably, R = H for the compounds of formula (I). Several embodiments of compounds of formula (I) are described below:
a) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, optionally substituted by a
i) hydroxyl;
According to this embodiment, the particularly preferred compounds are the compounds 1 , 10, 12, 13, 17, 19, 20, 24, 26 and 27. b) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, interrupted by an oxygen atom and optionally substituted by a
i) hydroxyl;
According to this embodiment, the particularly preferred compounds are the compounds 44, 45 and 46. c) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by
vi) one or two identical C(0)OR16 groups,
and optionally substituted by a group chosen from
ii) -SR15,
ix) phenyl, optionally being substituted by a hydroxyl, and
ix) a heteroaryl,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl hydrocarbon group and a branched (C3-Cio)alkyl group, and
R15 being a saturated linear (Ci-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the compounds 5, 6, 7, 15, 16, 22, 38, 40, 41 , 42 and 47. d) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by a group chosen from iii) -NR16R17,
ix) phenyl, optionally being substituted by a hydroxyl and/or a (Ci-Cs ix) a heteroaryl having from 5 to 12 ring members, comprising an oxygen atom,
x) a saturated heterocycle having from 5 to 8 ring members, comprising one or two oxygen atoms, optionally substituted by one or two (Ci-C4)alkyl radicals,
xii) a (C3-Cs)cycloalkyl,
R16 and R17, which are identical or different, being chosen from H, a saturated linear (Ci-Cio)alkyl group and an acetyl;
According to this embodiment, the particularly preferred compounds are the compounds 21 , 25, 28, 34, 35, 48, 49 and 51. e) R = H, Y = -NAR", R" = H,
A = branched (C3-Cio)alkyl, optionally substituted by a group chosen from i) hydroxyl,
vi) a COOR16 group,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl group and a branched (C3-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the compounds 2, 3, 4, 8, 9, 14, 18 and 23. f) R = H, Y = -NAR", R" = H, and
A = cyclic (C3-Cs)alkyl or
A = phenyl optionally substituted by a hydroxyl;
According to this embodiment, the particularly preferred compounds are the compounds 1 1 , 36 and 37. g) R = H, Y = -NAR", and
A and R' ' form, with the nitrogen atom which carries them, a saturated 5- to 8- membered heterocycle, optionally comprising an oxygen atom and optionally being substituted by a C(0)OT group, T denoting a saturated linear (Ci-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the compounds 29, 32 and 39. h) R = H, Y = -NAR", and
A denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR16,
R16 being a saturated linear (Ci-Cio)alkyl group; and
R" denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by one or two groups chosen from i) hydroxyl,
vi) -COOR26,
R26 being a saturated linear (Ci-Cio)alkyl group;
According to this embodiment, the particularly preferred compounds are the compounds 30, 31 , 33 and 50. j) R = acetyl, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl;
According to this embodiment, the particularly preferred compound is the compound 43. k) R = H, Y = -NAR", R" = H, and
A = -NR12R13 or
A = -OR14,
R12 and R13, which are identical, denoting a radical chosen from: a) -H and
b) a saturated linear (Ci-Cio)alkyl group;
R14 denoting a radical chosen from:
a) -H,
b) a saturated linear (Ci-Cio)alkyl group substituted by a phenyl;
According to this embodiment, the particularly preferred compounds are the compounds 52, 53, 54 and 55.
1) R = H, Y = -OR', R' = saturated linear (Ci-Cio)alkyl or a branched (C3-Cio)alkyl group, optionally interrupted by an oxygen atom and optionally substituted by one or two
i) hydroxy Is.
According to this embodiment, the particularly preferred compounds are the compounds 56 and 61.
Examples of compounds of formula (I) of the invention are collated in Table I below.
Table I
The numbers of the table correspond to the numbers used in the examples below.
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Their salts, their solvates, their isomers and their racemates also form part of the invention, taken alone or as mixtures. Among these compounds, the most particularly preferred compounds in the context of the present invention are the following: compounds 1 to 37, 39, 44 and 56, and their salts, their solvates, their isomers and their racemates, taken alone or as mixtures.
The compounds of the invention can be prepared according to the following
Scheme 1 :
Scheme 1
Figure imgf000026_0001
Acetylation
Figure imgf000026_0002
The process according to this Scheme 1 comprises the following stages:
a) reaction of resorcinol (Al) with itaconic acid (B) or its anhydride (Β') of its esters of formula (Bl)
Figure imgf000026_0003
B1
in which Ri denotes H or a linear (Ci-C6)alkyl group or a branched (C3- C6)alkyl group, in order to form a compound C, b) reduction of this compound C, in order to result in the intermediate (III), then
c) reaction of the intermediate (III) with a derivative YH, in which Y is as defined above, in order to access the compounds (I).
An alternative form consists in treating (III) with an alcohol ROH, in order to result in the compounds (IV), which, by reaction with YH, result in the compounds of formula (I).
The final stage is optionally an acetylation reaction (compounds of formula (I) for which R = acetyl).
Another subject-matter of the invention is the compound of formula (III) and the compound of formula (IV)
Figure imgf000027_0001
in which R denotes H or a linear (Ci-C6)alkyl group or a branched (C3-C6)alkyl group.
Preferably, according to the preceding scheme, ROH denotes ethanol and the R radical of the compound of formula (IV) denotes the ethyl radical.
The reaction of resorcinol (Al) with itaconic acid (B) or its anhydride (Β') or one of its esters of formula (B l) which are described above, in order to form the compound C, is carried out in particular in the presence of an organic solvent which can be chosen from toluene, tetrahydrofuran, heptane, isooctane, methyltetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate, isododecane and their mixtures, in particular at a temperature of between 15 and 200°C, optionally in the presence of a catalyst (acidic or basic) as described in the publications: Synthesis of 7- hydroxycoumarins by Pechmann reaction using Nafion resin/silica nanocomposites as catalysts: Laufer MC, Hausmann H and Holderich WF, J. of Catalysis, 2003, 218, 315- 320; Synthesis of 7-hydroxycoumarins catalysed by solid acid catalysts: Hoefnagel A, Gunnewegh E, Downing R and van Bekkum H, J. Chem. Soc, Chem. Commun., 1995, 225-226; in particular in the presence of an acid catalyst, such as methanesulfonic acid, triflic acid, para-toluenesulfonic acid or sulfonic resins, such as the Dowex® products or the Amberlyst® products (sold by Aldrich).
The compounds (Bl) can be obtained in a known way by selective esterification in an acidic medium of itaconic acid with one or more alcohols of formula ROH, as described in the literature (Selective esterification of non-conjugated carboxylic acids in the presence of conjugated or aromatic carboxylic acids over active carbon supported methanesulfonic acid; Feng, Ze Wang, Zhao, Xin Qi and Bi, Hua, Science in China, Series B: Chemistry (2008), 1(10), 990-992 / An efficient and regiospecific esterification of dioic acids using PTSA; Devi, A. Rama and Rajaram, S., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (2000), 39B(4), 294-296 / A simple method for the preparation of monomethyl esters of dicarboxylic acids by selective esterification of the nonconjugated carboxyl group in the presence of an aromatic or conjugated carboxyl group; Ram, Ram N. and Meher, Nabin Kumar; Journal of Chemical Research, Synopses (2000), (6), 282-283).
According to a specific embodiment of the process of synthesis, when the R group of the compound C denotes H, the compound of formula (I) can be obtained by activation of the acid C according to the known methods for the activation of acids, in particular described in Comprehensive Organic Transformations by R. Larock, Wiley VCH Ed., in the chapter Interconversion of nitriles, carboxylic acids and derivatives.
Mention may be made, as acid activation method, of:
- the intermediate formation of acid chloride (for example by using thionyl or oxalyl chloride, or l-chloro-N,N,2-trimethyl-l-propenamine),
- the intermediate formation of mixed anhydride (for example by using a C2-C6 alkyl chloroformate, such as isobutyl chloroformate, in the presence of a base, such as, for example, triethylamine or diisopropylethylamine),
- the intermediate formation of carbamimidate or of acylphosphonate (for example by using carbodiimides or diethyl cyanophosphate; Phosphorus in organic synthesis-XI, Amino acids and peptides-XXI, Reaction of diethyl phosphorocyanidate with carboxylic acids. A new synthesis of carboxylic esters and amides, Tetrahedron, 32, 1976, 2211-2217).
The compound C in the acid form can be subjected to a reduction using hydride in order to result in the compound of formula (III) after acid treatment, according to the following Scheme 2.
Scheme 2
Figure imgf000029_0001
C
This reduction can be carried out between -30 and +60°C in protic or aprotic solvents (tetrahydrofuran, dioxane, ethanol, methanol) with metal hydride donors, such as sodium borohydride, sodium triacetoxyborohydride or diisobutylaluminium hydride.
The reaction of the compound of formula (III) with a compound of formula YH can be carried out according to the following Scheme 3.
Scheme 3
Figure imgf000029_0002
This reaction can optionally be carried out in the presence of an organic solvent, in particular tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2- methyltetrahydrofuran, dichloromethane, toluene, methanol or ethanol,
optionally in the presence of a catalyst chosen from acid catalysts of Lewis or Bronsted type or basic catalysts, such as potassium carbonate, triethylamine or diisopropy lethy lamine ; optionally by heating to a temperature of between 15°C and 200°C, in particular between 30°C and 150°C.
It should be noted that the lactone (III) can be in equilibrium with the ethyl ester form (III') in the presence of ethanol. The acyclic ester can then react with YH compounds in order to result in the compounds (I).
The compounds of formula (I) for which R denotes an acetyl group can be obtained by acetylation of compounds of formula (I) for which R = H.
The acetylation reaction can be carried out with acetic anhydride or acetyl chloride, in particular in the presence of an aprotic solvent, such as toluene, pyridine or tetrahydrofuran.
The acetylation reaction can be selective by employing protective groups on the functional groups which must not be acetylated and by then carrying out a deprotection reaction, according to the known techniques of organic synthesis.
All of these stages can also resort to protection/deprotection strategies normally used in organic chemistry and compiled in the work "Protecting Groups in Organic Synthesis", Greene and Wuts, Wiley Interscience, as a function of the nature of the R', A and R" radicals.
In addition, when the final compounds (I) exhibit a free carboxylic acid on the A or R" radical, these compounds can be obtained by saponification using inorganic bases, such as, for example, NaOH or LiOH, in the presence of protic or aprotic solvents, such as, for example, ethanol or tetrahydrofuran or water, at temperatures varying between 0 and 100°C. The salts obtained are then re-acidified in the presence of conventional inorganic or organic acids, such as, for example, hydrochloric acid or citric acid.
The compounds of formula (I) according to the invention have a very particular application in the cosmetics field.
The composition according to the invention comprises, in a physiologically acceptable medium, a compound of formula (I) as described above.
The term "physiologically acceptable medium" is understood to mean a medium compatible with human keratinous substances, such as the skin of the body or of the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and/or the hair.
The compound (I) can be present in the composition according to the invention in an amount which can be between 0.01% and 10% by weight, preferably between 0.1% and 5% by weight, in particular from 0.5% to 3% by weight, with respect to the total weight of the composition.
The composition according to the invention is advantageously a cosmetic composition: it can comprise adjuvants normally employed in the cosmetics field.
Mention may in particular be made of water, organic solvents, in particular C2-
C6 alcohols, oils, in particular hydrocarbon oils or silicone oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers, cosmetic active agents, UV screening agents, polymers, thickeners, preservatives, fragrances, bactericides, ceramides, odour absorbers or antioxidants.
These optional cosmetic adjuvants can be present in the composition in a proportion of 0.001% to 80%> by weight, in particular of 0.1 % to 40%> by weight, with respect to the total weight of the composition. In any case, these adjuvants, and their proportions, will be chosen by a person skilled in the art so that the advantageous properties of the compounds according to the invention are not, or not substantially, detrimentally affected by the envisaged addition.
As active agents, it will be advantageous to introduce, into the composition according to the invention, at least one compound chosen from: desquamating agents; soothing agents; organic or inorganic photoprotective agents; moisturizing agents; depigmenting agents; antiglycation agents; NO-synthase inhibitors; agents which stimulate the synthesis of dermal or epidermal macromolecules and/or which prevent their decomposition; agents which stimulate the proliferation of fibroblasts and/or keratinocytes or which stimulate the differentiation of keratinocytes; muscle-relaxing agents and/or dermo-decontracting agents; tightening agents; agents for combating pollution and/or free radicals; agents which act on the microcirculation; agents which act on the energy metabolism of cells; and their mixtures.
Examples of such additional compounds are: retinol and its derivatives, such as retinyl palmitate; ascorbic acid and its derivatives, such as magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and its derivatives, such as tocopheryl acetate; nicotinic acid and its precursors, such as nicotinamide; ubiquinone; glutathione and its precursors, such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and in particular plant proteins and their hydro lysates, and also phyto hormones; marine extracts, such as algal extracts; bacterial extracts; sapogenins, such as diosgenin, and wild yam extracts comprising same; ceramides; hydroxy acids, such as salicylic acid and 5-(n- octanoyl)salicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acylated derivatives; manganese salts and magnesium salts, in particular gluconates; and their mixtures.
The term "desquamating agent" is understood to mean any compound capable of having an effect:
- either directly on desquamation by promoting exfoliation, such as β-hydroxy acids, in particular salicylic acid and its derivatives (including 5-(n-octanoyl)salicylic acid); a-hydroxy acids, such as gly colic, citric, lactic, tartaric, malic or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; or resveratrol;
- or on the enzymes involved in desquamation or decomposition of the corneodesmosomes, such as glycosidases, stratum corneum chymotryptic enzyme (SCCE) or indeed even other proteases (trypsin, chymotrypsin-like). Mention may be made of agents which chelate inorganic salts: EDTA; N-acyl-N,N',N'-ethylenediaminetriacetic acid; amino sulfonic compounds, in particular N-(2-hydroxyethyl)piperazine-N'-2- ethanesulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid (procysteine) derivatives; derivatives of a-amino acids of glycine type (such as described in EP 0 852 949, and also sodium methyl glycine diacetate, sold by BASF under the trade name Trilon M); honey; or sugar derivatives, such as O-octanoyl-6-D-maltose and N- acetylglucosamine.
The desquamating agents are generally present in the composition according to the invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from 0.1% to 10% by weight, with respect to the total weight of the composition.
Mention may be made, as soothing agents which can be used in the composition according to the invention, of pentacyclic triterpenes and extracts of plants (for example Glycyrrhiza glabra) comprising the same, such as β-glycyrrhetinic acid and its salts and/or its derivatives (glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate, 3-(stearoyloxy)glycyrrhetic acid), ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts, a Paeonia suffruticosa and/or lactiflora extract, salicylic acid salts and in particular zinc salicylate, phycosaccharides from Codif, a Laminaria saccharina extract, canola oil, bisabolol, camomile extracts, allantoin, Sepivital EPC (phosphoric diester of vitamins E and C) from Seppic, Ω-3 unsaturated oils, such as musk rose oil, blackcurrant oil, echium oil or fish oil, plankton extracts, capryloyl glycine, Seppicalm VG (sodium palmitoylproline and Nymphaea alba) from Seppic, a Pygeum extract, a Boswellia serrata extract, a Centipeda cunninghamii extract, a Helianthus annuus extract, a Linum usitatissimum extract, tocotrienols, Cola nitida extracts, piperonal, a clove extract, an Epilobium angustifolium extract, aloe vera, a Bacopa moniera extract, phytosterols, cortisone, hydrocortisone, indomethacin and betamethasone.
The soothing agents are generally present in the composition according to the invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from 0.1 %> to 10%) by weight, with respect to the total weight of the composition.
The organic photoprotective agents are chosen in particular from anthranilates; cinnamic derivatives; dibenzoylmethane derivatives; salicylic derivatives; camphor derivatives; triazine derivatives, such as those described in Patent Applications US 4 367 390, EP 863 145, EP 517 104, EP 570 838, EP 796 851, EP 775 698, EP 878 469, EP 933 376, EP 507 691, EP 507 692, EP 790 243 and EP 944 624; benzophenone derivatives; β,β-diphenylacrylate derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzazolyl derivatives, such as described in Patents EP 669 323 and US 2 463 264; p-aminobenzoic acid (PABA) derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives, such as described in Applications US 5 237 071, US 5 166 355, GB 2 303 549, DE19726184 and EP 893 119; screening polymers and screening silicones, such as those described in particular in Application WO- 93/04665; dimers derived from a-alkylstyrene, such as those described in Patent Application DE19855649; and merocyanine derivatives, such as those described in Applications WO 2011/113719 and FR 2 957 251.
The inorganic photoprotective agents can be chosen in particular from coated or non-coated metal oxide pigments or nanopigments (mean size of the primary particles generally of between 5 nm and 100 nm, preferably between 10 nm and 50 nm), such as, for example, titanium oxide (amorphous or crystallized in rutile and/or anatase form), iron oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments, which are all well- known UV photoprotective agents. Conventional coating agents are furthermore alumina and/or aluminium stearate. Such coated or non-coated metal oxide nanopigments are described in particular in Patent Applications EP 518 772 and EP 518 773. The photoprotective agents are generally present in the composition according to the invention in proportions ranging from 0.1% to 20% by weight, preferably ranging from 0.2% to 15% by weight, with respect to the total weight of the composition.
The composition according to the invention can be provided in all the formulation forms normally used in the cosmetics field and in particular in the form of an aqueous or aqueous/alcoholic solution, which is optionally gelled, of a dispersion of the lotion type, optionally comprising two phases, of an oil-in-water or water-in-oil or multiple (W/O/W or 0/W/O, for example) emulsion, of an aqueous gel, of a dispersion of oil in an aqueous phase using spherules, it being possible for these spherules to be polymeric nanoparticles, such as nanospheres and nanocapsules or better still lipid vesicles of ionic and/or non-ionic type, or of an aqueous or oily gel. These compositions are prepared according to the usual methods. Use is preferably made, according to this invention, of a composition in the form of an emulsion, in particular an oil-in-water emulsion.
The composition according to the invention can constitute a composition for caring for the skin and in particular a cleansing, protecting, treating or care cream for the face, for the hands, for the feet, for the major anatomical folds or for the body (for example, day creams, night creams, make-up-removing creams, foundation creams or anti- sun creams); a fluid foundation; a make-up-removing milk, a protective or care body milk or an anti-sun milk; or a lotion, gel or mousse for caring for the skin, such as a cleansing lotion.
The invention is illustrated in more detail by the following non- limiting examples.
Example 1: attainment of intermediates
1.1. Attainment of the lactone C in the acid form C 1
Figure imgf000034_0001
10 g of resorcinol and 11.8 g of itaconic acid were dissolved in 150 ml of a toluene/dioxane mixture (1/1 ratio by volume) in the presence of Amberlyst 15 resin from Aldrich in a round-bottomed flask equipped with a Dean and Stark apparatus. The reaction medium was heated at 100°C for 3 hours. After cooling, the crude reaction product was filtered and the filtrate was concentrated under vacuum. The crude product was recrystallized under hot conditions from ethyl acetate. 10 g of a white powder corresponding to the expected product were obtained (yield of 50%).
Melting point: 174-175°C. The 1H NMR and mass spectra are in accordance with the structure of the expected product.
1.2. Synthesis of 4-(2,4-dihydroxybenzyl)dihydrofuran-2(3H)-one of formula
Figure imgf000035_0001
C1
6.8 g of sodium borohydride (2 eq.) are added to a solution of 20 g of the intermediate CI in 100 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 5 days. Water is added and the organic phase is extracted by 3 times with ethyl acetate. After concentrating under vacuum, the crude reaction product is placed in a heated desiccator overnight. The next day, the crude product is triturated with 50 ml of dichloromethane. A pink precipitate is formed which, after filtration on a sintered glass filter, gives the compound of formula (III) with a yield of 77%.
The 1H NMR and mass spectra are in accordance with the structure of the expected product (III).
The compound of formula (III) is subsequently reacted according to Scheme 3 described above with the YH compound, used as reactant and solvent when YH is liquid, for example when YH is an amine (3 equivalents), and then the reaction medium is brought to 60°C for 2h.
In the case where YH is solid, methyltetrahydrofuran can be added in a sufficient amount to dissolve the reaction medium.
At the end of the reaction, the reaction medium is concentrated under vacuum. The crude product is dissolved in methyltetrahydrofuran, washed with a 0.1N hydrochloric acid solution and then washed with water. The organic phase is collected, dried over sodium sulfate and concentrated under vacuum. The crude product is purified on a chromatography column to give the expected product.
The examples below illustrate these subsequent stages.
Example 2: synthesis of compound 2:
Figure imgf000036_0001
15 g of the compound of formula (III) are introduced, with 3.5 equivalents of ethyl leucinate (49 g in the hydrochloride form before neutralization), into a round- bottomed flask. The reaction medium is heated at 145°C for 5 hours. After cooling, the reaction medium is diluted in ethyl acetate and the organic phase is washed with a IN hydrochloric acid solution and then with a saturated sodium chloride solution. After drying the organic phase over sodium sulfate and concentrating under vacuum, an orange- coloured wax is obtained (18 g). The latter is purified on a silica column (eluent dichloromethane:methanol 9: 1). After collecting the fractions of interest and concentrating, 12.8 g of a pale yellow solid are obtained, corresponding to compound 2 in the form of a mixture of 2 diastereoisomers in a 53/47 ratio determined by 1H NMR. (48%).
The 1H NMR and mass spectra are in accordance with the structure of the expected mixture of diastereoisomers.
Example 3: synthesis of compound 6:
Figure imgf000036_0002
1.6 g of the compound of formula (IV) are introduced, with 9.6 g of ethyl tyrosinate, into a round-bottomed flask. The reaction medium is heated at 130°C for 4 hours. After cooling, the reaction medium is diluted in 100 ml of methanol and filtered. The filtrate is concentrated under vacuum to result, after purification on a silica column (eluent dichloromethane/methanol 30/1), in 1.5 g of a white solid, corresponding to compound 6 (yield 47%) in the form of a mixture of 2 diastereoisomers in a 55/45 ratio determined by 1H NMR. (48%)
The 1H NMR and mass spectra are in accordance with the structure of the expected mixture of diastereoisomers.
Example 4: synthesis of compound 5 (saponification of compound 6)
Figure imgf000037_0001
1 g of compound 6 is placed in 5 ml of ethanol in the presence of 480 mg of lithium hydroxide. After stirring for 14 hours, the solvent is concentrated under vacuum and the reaction medium is acidified to pH 2 using IN hydrochloric acid in the presence of ethyl acetate. After extracting the aqueous phase twice with ethyl acetate and then drying over magnesium sulfate, the combined organic phases are concentrated under vacuum. The crude product obtained is purified on a silica column (eluent dichloromethane/methanol 20/1) to result in 260 mg of a yellow solid (27% yield) corresponding to compound 5.
The 1H NMR and mass spectra are in accordance with the structure of the expected product.
Examples 5 to 33: Synthesis of the compounds
The same procedure was carried out as in the examples described above, using a different amine specified in the table below:
Compound Final stage
Structure Amine YH
No. yield (%)
1 Butylamine 54
2 Ethyl leucinate 48
3 Ethyl valinate 62
Figure imgf000037_0002
OH H OH
Ethyl valinate, followed
4 30
o by saponification
- HO J L Jl OH
Figure imgf000038_0001
Figure imgf000039_0001
Example 34: Example of separation of the diastereoisomers and characterization of the latter
Performance of a separation of compound 2 using preparative HPLC chromatography Instrument: SFC-80 (Thar, Waters)
Column: (R, R)WHELK-01 50*250 mm 5 μιη (Regis)
Column temperature: 40°C Mobile phase: C02/ Isopropanol = 70/30
Flow: 150 g/min
Back pressure: 100 bar
Cycle by injection: 4.4 min
Amount at each injection: 1 16 mg
Retention time of the first diastereoisomer (2-a): 3.87 min
Retention time of the second diastereoisomer (2-b): 4.55 min
The 1H NMR and mass spectra are in accordance with the structures of the 2 expected products.
Example 35: Demonstration of the activity with regard to constitutive melanogenesis
A biological test demonstrated the depigmenting activity of the compounds of formula (I).
The modulating effect on melanogenesis of compound 2 was measured according to the method described in Patent FR-A-2 734 825, and in the paper by R. Schmidt, P. Krien and M. Regnier, Anal. Biochem., 235(2), 113-18, 1996. This test is carried out on a coculture of keratinocytes and melanocytes.
For the test compound, the following were determined:
the cytotoxicity, by estimating the incorporation of leucine, or by the use of Alamar Blue
the inhibitory activity on melanin synthesis, by estimating the ratio of the incorporation of thiouracil to the incorporation of leucine, relative to 100% for the control (the control corresponds to the test carried out without test compound). The IC50 (concentration for which 50% of the synthesis of the melanin is inhibited) values were determined.
The test was also carried out with arbutin and kojic acid, which are known depigmenting compounds.
The results are collated in the following table:
Figure imgf000041_0001
on-cytotox c . μ
The compounds according to the invention are thus shown to be effective in inhibiting melanogenesis and are furthermore more effective than arbutin and kojic acid.
Example 36: Use of a cosmetic formulation
A depigmenting gel for the skin is prepared, comprising (% by weight):
Compound 2 (Example 1) 2%
Carbomer (Carbopol 981 from Lubrizol) 1%
Preservative q.s.
Water q.s. for 100%
The composition, applied to the skin, makes it possible to soften brown blemishes.
A similar composition is prepared with compound 1.

Claims

1. Compound of formula (I)
Figure imgf000042_0001
in which:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR5,
ii) -SR5,
iii) -NR6R7,
iv) -C(0)NHR6,
v) -C(0)NR6R7,
vi) -C(0)OR6,
vii) -NHC(0)NHR6,
viii) -C(0)(Ci-C4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group; c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from
· H, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group,
R6 and R7, which are identical or different, being chosen from
· H,
• an acetyl radical, and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group,
it being possible for R6 and R7 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
A denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR15,
ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
v) -C(0)NR16R17,
vi) -C(0)OR16,
vii) -NHC(0)NHR16, viii) -C(0)(Ci-C4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group,
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; and
xi) -NH-C=NH(NH2) (guanidine group); c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group; d) -NR12R13; e) -OR14; f) -C(0)NHR14; g) -C(0)(Ci-Cio)alkyl; R12 and R13, which are identical or different, denoting a radical chosen from:
• -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different -OR 15 groups, and
• an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group,
it being possible for R12 and R13 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C4)alkoxy group;
R14 denoting a radical chosen from:
· -H,
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
vi) -C(0)OR16, and
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group, and
• an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;
R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group; R16 and R17, which are identical or different, being chosen from H; an acetyl radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H;
b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR25,
ii) -SR25,
iii) -NR26R27,
iv) -C(0)NHR26,
v) -C(0)NR26R27,
vi) -C(0)OR26,
vii) -NHC(0)NHR26,
viii) -C(0)(Ci-C4)alkyl,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; and
c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R25 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group;
R26 and R27, which are identical or different, being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3- Cio)alkyl group or a (C3-C8)cycloalkyl group; a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R26 and R27 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-Cio)alkyl, hydroxy(Ci- Cio)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-Cio)alkyl group and a branched (C3-Cio)alkyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
2. Compound according to the preceding claim, in which:
R denotes a hydrogen atom or an acetyl group;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H; b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different -OR5 groups; and c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group;
R5 being chosen from H and a saturated linear (Ci-C4)alkyl group;
A denotes a radical chosen from:
a) -H; b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C2-C2o)alkyl group, a branched (C3-C2o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:
i) -OR15, ii) -SR15,
iii) -NR16R17,
iv) -C(0)NHR16,
vi) -C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and
x) a saturated or unsaturated nonaromatic (C3-Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci-C4)alkyl group; c) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-Cs)alkyl group; d) -NR12R13; and e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H;
• a saturated linear (Ci-C4)alkyl group; and
• a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group; and
it being possible for R12 and R13 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C4)alkoxy group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-Cio)alkyl group which can optionally be substituted by one to three identical or different groups chosen from a saturated linear (Ci-Cio)alkyl group, optionally substituted by one or more phenyl radicals, it being possible for the said phenyl radicals to be optionally substituted by one to three identical or different groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group; R15 being chosen from H, a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group and a (C3-Cs)cycloalkyl group;
R16 and R17, which are identical or different, being chosen from
· H;
• an acetyl radical; and
• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group;
it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-C2o)alkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different -OR25 groups;
R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-C4)alkyl, hydro xy(Ci- C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-C6)alkyl group and a branched (C3-C6)alkyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
3. Compound according to either one of the preceding claims, in which:
R denotes a hydrogen atom;
Y denotes a radical chosen from OR' or NAR";
R' denotes a radical chosen from:
a) -H; and b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three oxygen atoms, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from hydroxyl, methoxy and ethoxy;
A denotes a radical chosen from:
a) -H; b) a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three oxygen atoms, it being possible for the said groups to be optionally substituted by one or more identical or different groups chosen from:
i) -OR15,
ii) -SR15, preferably SMe,
iii) -NR16R17,
vi) -C(0)OR16,
ix) an aryl or heteroaryl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, preferably an imidazole or indole radical or a phenyl radical optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, particularly preferably an imidazolyl, indolyl or phenyl group, and
x) a saturated or unsaturated nonaromatic, preferably saturated, (C3- Cs)cycloalkyl or heterocycle group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group;
c) a phenyl group optionally substituted by one to three groups chosen from hydroxyl, methoxy and ethoxy; d) -NR12R13; and e) -OR14;
R12 and R13, which are identical or different, denoting a radical chosen from:
• -H,
• a saturated linear (Ci-C4)alkyl group, and
• a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group;
R12 and R13 preferably denoting a hydrogen atom or a (Ci-C4)alkyl group;
R14 denoting a radical chosen from:
• -H, and
• a saturated linear (Ci-C4)alkyl group, optionally substituted by a phenyl radical, such as the benzyl group;
R15 being chosen from H, a saturated linear (Ci-C4)alkyl group and a branched (C3-C4)alkyl group;
R16 and R17, which are identical or different, being chosen from H; an acetyl radical; a saturated linear (Ci-Cio)alkyl group, an unsaturated (C2-Cio)alkyl group, a branched (C3-Cio)alkyl group or a (C3-C8)cycloalkyl group; and a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci-C4)alkyl group; it being possible for R16 and R17 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle comprising one to three heteroatoms or groups chosen from N, O and -C(O)-, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;
R" denotes a radical chosen from:
a) -H; and
b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-Cio)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different -OR25 groups;
R25 being chosen from H and a saturated linear (Ci-Cio)alkyl group; it being understood that A and R" can form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a group chosen from (Ci-C4)alkyl, hydro xy(Ci- C4)alkyl and C(0)OT, T denoting a group chosen from H, a saturated linear (Ci-C6)alkyl group and a branched (C3-Ce)alkyl group, the said heterocycle preferably being a piperidinyl or morpholinyl group; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.
4. Compound according to any one of the preceding claims, in which R = H.
5. Compound according to any one of the preceding claims, in which the compound has the following meaning:
a) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, optionally substituted by a
i) hydroxyl; b) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, interrupted by an oxygen atom and optionally substituted by a i) hydroxyl; c) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by
vi) one or two identical COOR16 groups,
and optionally substituted by a group chosen from
ii) -SR15,
ix) phenyl, optionally being substituted by a hydroxyl, and
ix) a heteroaryl having from 5 to 12 ring members, comprising one or two heteroatoms chosen from O, N or S,
R16 being chosen from H, a saturated linear (Ci-Cio)alkyl hydrocarbon group and a branched (C3-Cio)alkyl group, and
R15 being a saturated linear (Ci-Cio)alkyl group; d) R = H, Y = -NAR", R" = H,
A = saturated linear (Ci-Cio)alkyl, substituted by a group chosen from iii) -NR16R17,
ix) phenyl, optionally being substituted by a hydroxyl and/or a (Ci-Cs)alkoxy radical,
ix) a heteroaryl having from 5 to 12 ring members, comprising an oxygen atom,
x) a saturated heterocycle having from 5 to 8 ring members, comprising one or two oxygen atoms, optionally substituted by one or two (Ci-C4)alkyl radicals, xii) a (C3-Cs)cycloalkyl,
R16 and R17, which are identical or different, being chosen from H, a saturated linear (Ci-Cio)alkyl group and an acetyl; e) R = H, Y = -NAR", R" = H,
A = branched (C3-Cio)alkyl, optionally substituted by a group chosen from i) hydroxyl,
vi) a COOR16 group, R16 being chosen from H, a saturated linear (Ci-Cio)alkyl group and a branched (C3-Cio)alkyl group; f) R = H, Y = -NAR", R" = H, and
A = cyclic (C3-C8)alkyl or
A = phenyl optionally substituted by a hydroxyl; g) R = H, Y = -NAR", and
A and R' ' form, with the nitrogen atom which carries them, a saturated 5- to 8- membered heterocycle, optionally comprising an oxygen atom and optionally being substituted by a C(0)OT group, T denoting a saturated linear (Ci- Cio)alkyl group; h) R = H, Y = -NAR", and
A denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR16,
R16 being a saturated linear (Ci-Cio)alkyl group; and
R" denotes a saturated linear (Ci-Cio)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by one or two groups chosen from
i) hydroxyl,
vi) -COOR26,
R26 being a saturated linear (Ci-Cio)alkyl group; j) R = acetyl, Y = -NAR' ' , R" = H,
A = saturated linear (Ci-Cio)alkyl; k) R = H, Y = -NAR", R" = H, and
A = -NR12R13 or
A = -OR14,
R12 and R13, which are identical, denoting a radical chosen from: a) -H and
b) a saturated linear (Ci-Cio)alkyl group;
R14 denoting a radical chosen from:
a) -H,
b) a saturated linear (Ci-Cio)alkyl group substituted by a phenyl; 1) R = H, Y = -OR\
R' = saturated linear (Ci-Cio)alkyl or a branched (C3-Cio)alkyl group, optionally interrupted by an oxygen atom and optionally substituted by one or two
i) hydroxy Is.
6. Compound according to any one of Claims 1 to 3, chosen from the following compounds:
N-butyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
ethyl N- [3 -(2,4-dihydroxybenzyl)-4-hydroxybutanoyl] leucinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]valinate,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]valine,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]tyrosine,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]tyrosinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glycinate,
3 -(2,4-dihydroxybenzyl)-4-hydroxy-N-( 1 -hydroxy-3 -methylbutan-2-yl)butanamide,
3 -(2,4-dihydroxybenzyl)-4-hydroxy-N-( 1 -hydroxy-4-methylpentan-2-yl)butanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-propylbutanamide,
N-cyclopentyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(2-hydroxyethyl)butanamide,
3-(2,4-dihydroxybenzyl)-N-ethyl-4-hydroxybutanamide,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]leucine,
N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glycine,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]phenylalaninate,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-octylbutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(6-methylheptyl)butanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-pentylbutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-nonylbutanamide, N-(cyclohexylmethyl)-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide, ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]-D-tryptophanate,
3-(2,4-dihydroxybenzyl)-N-(2-ethylhexyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-hexyl-4-hydroxybutanamide,
N-(2-cyclohexylethyl)-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-heptyl-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-(2,3-dihydroxypropyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N-[(2,2-dimethyl-l ,3-dioxolan-4-yl)methyl]-4- hydroxybutanamide,
3 -(2,4-dihydroxybenzyl)-4-hydroxy- 1 -(morpholin-4-yl)butan- 1 -one,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N,N-bis(2-hydroxyethyl)butanamide,
3-(2,4-dihydroxybenzyl)-N,N-diethyl-4-hydroxybutanamide,
3 -(2,4-dihydroxybenzyl)-4-hydroxy- 1 -(piperidin- 1 -yl)butan- 1 -one,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]-N-methylglycinate,
N-benzyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-[2-(4-hydroxy-3- methoxyphenyl)ethyl]butanamide,
N-phenyl-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide,
3- (2,4-dihydroxybenzyl)-4-hydroxy-N-(4-hydroxyphenyl)butanamide, ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glutamate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]prolinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]histidinate,
ethyl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]methioninate,
propan-2-yl N-[3-(2,4-dihydroxybenzyl)-4-hydroxybutanoyl]glycinate,
4- {2-[(acetyloxy)methyl]-4-(butylamino)-4-oxobutyl}benzene-l,3-diyl diacetate, 3-(2,4-dihydroxybenzyl)-4-hydroxy-N-(3-methoxypropyl)butanamide,
3-(2,4-dihydroxybenzyl)-N-(2-ethoxyethyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N-[2-(2-hydroxyethoxy)ethyl]butanamide, ethyl 4- { [3 -(2,4-dihydroxybenzyl)-4-hydroxybutanoyl] amino } butanoate, 3-(2,4-dihydroxybenzyl)-N-[2-(dimethylamino)ethyl]-4-hydroxybutanamide, N-[2-(acetylamino)ethyl]-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide, 3-(2,4-dihydroxybenzyl)-4-hydroxy-N,N-bis(2-methoxyethyl)butanamide, 3-(2,4-dihydroxybenzyl)-N-(furan-2-ylmethyl)-4-hydroxybutanamide,
3-(2,4-dihydroxybenzyl)-N,4-dihydroxybutanamide,
N-(benzyloxy)-3-(2,4-dihydroxybenzyl)-4-hydroxybutanamide, 3-(2,4-dihydroxybenzyl)-4-hydroxybutanohydrazide,
3-(2,4-dihydroxybenzyl)-4-hydroxy-N',N'-dimethylbutanohydrazide,
ethyl 3 -(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
isopropyl 3 -(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
butyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
hexyl 3 -(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
2,3-dihydroxypropyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
2-methoxypropyl 3-(2,4-dihydroxybenzyl)-4-hydroxybutanoate,
and their salts, their solvates, their optical isomers, their racemates, taken alone or as mixtures.
7. Composition comprising, in a physiologically acceptable medium, a compound of formula (I) according to any one of the preceding claims.
8. Composition according to the preceding claim, characterized in that the compound of formula (I) is present in a content of between 0.01% and 10% by weight, preferably between 0.1% and 5% by weight, in particular from 0.5%> to 3% by weight, with respect to the total weight of the composition.
9. Composition according to either of Claims 7 and 8, characterized in that it comprises at least one adjuvant chosen from the group formed by: water, organic solvents, hydrocarbon oils, silicone oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers, cosmetic active agents, UV screening agents, polymers, thickeners, preservatives, fragrances, bactericides, ceramides, odour absorbers and antioxidants.
10. Composition according to any one of Claims 7 to 9, characterized in that it comprises at least one active agent chosen from: desquamating agents; soothing agents; organic or inorganic photoprotective agents; moisturizing agents; depigmenting agents; antiglycation agents; NO-synthase inhibitors; agents which stimulate the synthesis of dermal or epidermal macromolecules and/or which prevent their decomposition; agents which stimulate the proliferation of fibroblasts and/or keratinocytes or which stimulate the differentiation of keratinocytes; muscle-relaxing agents and/or dermo-decontracting agents; tightening agents; agents for combating pollution and/or free radicals; agents which act on the microcirculation; agents which act on the energy metabolism of cells; and their mixtures.
11. Non-therapeutic cosmetic method for depigmenting, lightening and/or whitening keratinous substances, in particular the skin, comprising the application of a composition according to any one of Claims 7 to 10.
12. Method according to the preceding claim, for depigmenting, lightening and/or whitening the skin.
13. Non-therapeutic cosmetic use of a compound of formula (I) as defined according to any one of Claims 1 to 6 as whitening, lightening and/or depigmenting agent for keratinous substances, in particular the skin.
14. Process for the preparation of the compounds of formula (I) according to one of Claims 1 to 6, comprising the following stages:
a) reaction of resorcinol (Al) with itaconic acid (B) or its anhydride (Β') or one of its esters of formula (Bl)
Figure imgf000058_0001
B1
in which Ri denotes H or a linear (Ci-C6)alkyl group or a branched (C3- C6)alkyl group, in order to form a compound C of formula
Figure imgf000058_0002
b) reduction of this compound C, in order to result in the intermediate (III) then
Figure imgf000058_0003
c) reaction of the intermediate (III) with a derivative YH, in which Y is as defined according to any one of Claims 1 to 5, in order to access the compounds (I).
15. Intermediate compounds of formulae (III) and (IV)
Figure imgf000058_0004
Figure imgf000059_0001
in which R denotes H or a linear (Ci-C6)alkyl group or a branched (C3-C6)alkyl group.
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